Vasoactive vasotocin derivatives

ABSTRACT

The present invention relates to new vasotocin derivatives with prolonged activity compared to previous vasotocin derivatives. In particular, the vasotocin derivatives of the present invention are of the formula (I) ##STR1## wherein Hmp is a 2-hydroxy-3-mercaptopropionic acid residue, ##STR2## Z is Phe or Tyr, Y is Hgn or Hci, X is a residue of the formula ##STR3## wherein Q is H, alanyl or L-2-aminobutyryl and n is 1, 2 or 3. The present invention also relates to pharmaceutical compositions containing these vasotocin derivatives.

The present invention relates to new vasotocin derivatives, morespecifically such vasotocin derivatives as differ from the nativehormone in that the vasotocin (VT) structure has been modified atpositions 1, 4, 8 and optionally 2.

The new VT derivatives are vasoactive, more particularly by specificallyraising the blood pressure, and in some cases have a considerablyprolonged effect.

BACKGROUND

The peptide hormone vasopressin, produced by the posterior lobe of thepituitary, mainly has two functions, that is the hormone has both anantidiuretic effect (reduced excretion of urine) and a contractingeffect on smooth muscles in the vascular wall, the latter effect causinga blood pressure increase and a reduced tendency to bleeding. Inclinical use, vasopressin thus has a non-specific effect of shortduration.

Today, there is on the market a vasopressin analog having a prolongedeffect, namely lysine-vasopressin extended in the N-terminal by threeamino acid residues. This vasopressin analog acts as a so-calledprohormone or hormonogen, i.e. it increases the duration of thevasopressin effect. The extended vasopressin analog has in itself a verysmall pharmacological effect which does not occur until the extraN-terminal amino acid residues are cleaved by enzymatic hydrolysis andfree lysine-vasopressin is formed. Besides the prolonged effect, such aprohormone is advantageous in that the risk of overdosage is minimizedby the limited enzyme capacity of the organism determining the plasmalevels of the liberated vasopressin. In this manner, it is possible toavoid excessively high plasma levels of vasopressin possibly leading toabnormally increased blood pressure which may harm the patient. Theabove-mentioned vasopressin analog however suffers from major drawbacksby having low potency and, like vasopressin, being non-specific.

There is a need for vasoconstrictive substances for use as bleedinginhibitors and in so-called orthostatic hypotension, i.e. conditions ofblood pressure drop following changes of body position. These agentsshould specifically increase blood pressure, thus having a lowantidiuretic effect in order to avoid water intoxication in patientssubjected to long-term treatment. Also, it is advantageous if theyexhibit an effect of long duration.

Recently, we have filed (on Oct. 7, 1987) a Swedish patent applicationSE 8703855-0 (corresponding to PCT/SE88/00509) comprising vasotocinderivatives having specific blood pressure increasing activity. Thevasotocin derivatives according to the present invention differstructurally from the vasotocin derivatives according to said priorSwedish patent application mainly in that they have a furthermodification at position 4 of the vasotocin structure, i.e. they havehomoglutamine or homocitrulline at position 4.

DESCRIPTION OF THE INVENTION

The present new vasoactive vasotocin derivatives specifically increaseblood pressure, i.e. they are pressor-specific, meaning a high ratio ofblood pressure to antidiuretic activity. In particular the antidiureticeffect (reduced excretion of urine) of the parent molecule iseliminated. Furthermore they have a considerably prolonged effect insome cases. The compounds according to the invention are intended to beused in a pharmaceutical composition for inhibiting bleeding and inconditions of blood pressure drop following changes of body position,so-called orthostatic hypotension, and also as general blood pressureincreasing agents. The VT derivatives according to the invention are ofthe formula (SEQ ID NO: 1). ##STR4## wherein Hmp=a2-hydroxy-3-mercaptopropionic acid residue, ##STR5## Z=phenylalanine(Phe) or tyrosine (Tyr) Y=homoglutamine (Hgn) or homocitrulline (Hci)##STR6## Q=H or from 1 to 3 amino acid residues of the same or differentnatural or unnatural L- or D-amino acids, and n is 1, 2 or 3.

The VT derivatives according to the invention can be presented in theform of pharmaceutical compositions in which at least one VT derivativeaccording to the invention is included as active ingredient, togetherwith pharmaceutically acceptable additives and/or diluents. Thepharmaceutical compositions according to the invention preferably are inthe form of preparations suitable for parenteral administration. Theyare suitably administered by injection, infusion or intranasalapplication. The diluent may be e.g. a physiological saline solution.

A pharmaceutical composition according to the invention may contain aspecifically blood pressure increasing derivative having a relativelyshort duration for providing an instant effect, in combination with aspecifically blood pressure increasing derivative having a long durationfor providing a prolongation of the effect.

PREPARATION OF THE VT DERIVATIVES ACCORDING TO THE INVENTION

The VT derivatives according to the invention can be prepared by methodsanalogous with those which are known in the peptide field.

For instance, the compounds according to the invention can be beprepared in conventional manner by coupling amino acids stepwise to oneanother in liquid phase, e.g. as disclosed by Law, H. B. & Du Vigneaud,V. in Journal of the American Chemical Society 82, (1960) 4579-4581,Zhuze, A. L., Jost, K., Kasafi'rek, E. & Rudinger, J. in Collection ofCzechoslovak Chemical Communications 29 (1964), 2648-2662, and modifiedby Larsson, L.-E., 5 Lindeberg, G., Melin, P. / Pliska, V. in Journal ofMedicinal Chemistry21, (1978), 352-356. The coupling of the amino acidsto one another, yielding so-called peptide bonds, can also be effectedwith a solid phase (generally a resin) as starting material to which theC-terminal of the first amino acid is coupled, whereupon the C-terminalof the next amino acid is coupled to the N-terminal of the first aminoacid and so on. Finally, the finished peptide is liberated from thesolid phase. In the Examples hereinbelow, this so-called solid phasetechnique has been used in accordance with the disclosure of Merrifield,R. B., J. Am. Chem. Soc. (1963) 85, 2149, Merrifield, R. B. Biochemistry(1964), 3, 1385 and Konig, W., Geiger, R., Chem. Bar. (1970), 103, 788.

GENERAL DESCRIPTION OF SYNTHESIS

All the VT derivatives prepared in the Examples given below weresynthesised on an APPLIED BIOSYSTEMS 430a PEPTIDE SYNTHESIZER using adouble coupling program with a termination step after the secondcoupling. The resin used was of 4-methylbenzhydrylamine type with atheoretical loading of 0.65 meq/g (Peninsula Laboratories Inc., USA).The final product of the synthesis was dried in vacuo overnight. Thepeptide was then cleaved from the resin by treatment with liquidhydrogen fluoride in the presence of anisole and ethyl-methyl-sulphideas scavengers (HF:anisole:EMS 10:05:05). After removal of hydrogenfluoride by evaporation, the resin was suspended in ethyl acetate (100ml) and filtered. The solid was washed on filter with additional ethylacetate (3×100 ml), and the cleaved peptide was extracted with aceticacid (100 ml). The extract was promptly diluted to a volume of 1.5 iwith 20% acetic acid in methanol and treated with 0.1M solution ofiodine in methanol until a faint brown colour remained. Then a DOWEX 1×8ion exchanger in acetate form (15 g) (Bio-Rad, Richmond, Calif.) wasadded and the mixture filtered. The filtrate was evaporated and theresidue freeze-dried from water. The product was then purified byreversed phase liquid chromatography on a column filled with KROMASIL®13μ (EKA Nobel, Surte, Sweden) in a suitable system containingacetonitrile in 0.1% trifluoroacetic acid water solution. The samplescollected from the column were analysed by analytical high performanceliquid chromatography (HPLC) (Spectra Physics Inc. USA 8800) equippedwith a VYDAC 5μ C18 column (Vydac Inc., USA). Fractions containing puresubstance were pooled, the solvent was evaporated and the productfreeze-dried from water. The final HPLC analysis was performed on readyproduct, and the structure of the peptide was confirmed by amino acidanalysis and fast atom bombardment mass spectrometry (FAB MS).

All amino acids used during the synthesis were L-amino acids, and theywere protected with a tert-butoxy-carbonyl group at the α-aminofunction. The side chains were protected as follows:

Hmp(Mob), Cys(Mob), Dab(Cbz).

The abbreviations within brackets are:

Cbz=carbobenzoxy;

Mob=4-methoxybensyl; and

Boc=t-butyloxycarbonyl

The amino acid derivatives were supplied by Bachem AG, Switzerland.

Further abbreviations used are:

Dab=L-2,4-diaminobutyric acid

Abu=L-2-aminobutyric acid

Hgn=homoglutamine

Hci=homocitrulline

Hmp=2-hydroxy-3-mercaptopropionic acid

OPfp=pentafluorophenyl ester

DIPEA=diisopropylethylamine

EXAMPLE 1

1-Hmp-2-Phe-4-Hgn-8-Dab-VT (SEQ ID NO: 2) [n=2 and Q=H]

The peptide was synthesised according to the general description.2-hydroxy-mercaptopropionic acid[S-(p-methoxy)benzyl] was used forposition 1. Purity (HPLC): 99.5% (18.4% acetonitrile in 0.1% TFA,retention time 9.13 rain at 1.5 ml/min, detection at 223 nm).

The structure was confirmed by amino acid analysis and FAB MS analysis.

EXAMPLE 2

1-Hmp-2-Phe-4-Hgn-8-Dab(Ala)-VT [n=2 and Q=Ala]

The oxidized and purified nonapeptideHmp-Phe-Ile-Hgn-Asn-Cys-Pro-Dab-Gly-NH₂ (SEQ ID NO: 2)(150 mg; preparedby solid phase method according to the general description) wasdissolved in DMF (2 ml) and previously formed Boc-Ala-OPfp (4equivalents) was added and pH was adjusted to 8-8.5 (DIPEA). Thereaction mixture was stirred overnight at room temperature. The productwas isolated by precipitation with ethyl acetate, filtration and dryingin vacuo.

The product was then treated with TFA/CH₂ Cl₂ 1:1 (20 ml), stirred for30 min, evaporated and then treated with diethyl ether (100 ml). Theprecipitation was separated by filtration and dried in vacuo.

The product was purified by reversed phase liquid chromatography.

Purity (HPLC): 99.8% (17.6% acetonitrile in 0.1% TFA, retention time8.56 min at 2 ml/min, detection at 223 nm).

The structure was confirmed by amino acid analysis and FAB MS analysis.

EXAMPLE 3

1-Hmp-2-Phe-4-Hgn-8-Dab(Abu)-VT [n=2 and Q=Abu]

The oxidized and purified nonapeptideHmp-Phe-Ile-Hgn-Asn-Cys-Pro-Dab-Gly-NH₂ (SEQ ID NO: 2) (100 mg; preparedby solid phase method according to the general description) wasdissolved in DMF (2 ml) and previously formed Boc-Abu-OPfp (4equivalents) was added and pH was adjusted to 8-8.5 (DIPEA). Thereaction mixture was stirred overnight at room temperature. The productwas isolated by precipitation with ethyl acetate, filtration and dryingin vacuo.

The product was then treated with TFA/CH₂ Cl₂ 1.1 (20 ml ), stirred for30 min, evaporated and then treated with diethyl ether (100 ml). Theprecipitation was separated by filtration and dried in vacuo.

The product was purified by reversed phase liquid chromatography.

Purity (HPLC): 99.5% (17.6% acetonitrile in 0.1% TFA, retention time9.82 min at 2 ml/min, detection at 223 nm).

The structure was confirmed by amino acid analysis and FAB MS analysis.

EXAMPLE 4

1-Hmp-2-Phe-4-Hci-8-Dab-VT (SEQ ID NO: 3) [n=2 and Q=H]

The peptide was synthesised according to the general description.2-hydroxy-mercaptopropionic acid[S-(p-methoxy)benzyl] was used forposition 1. Purity (HPLC): 98.5% (17.6% acetonitrile in 0.1% TFA,retention time 10.68 rain at 2 ml/min, detection at 223 nm).

The structure was confirmed by amino acid analysis and FAB MS analysis.

EXAMPLE 5

1-Hmp-2-Phe-4-Hci-8-Dab(Abu)-VT [n=2 and Q=Abu]

The oxidized and purified nonapeptideHmp-Phe-Ile-Hci-Asn-Cys-Pro-Dab-Gly-NH₂ (SEQ ID NO: 3) (100 mg; preparedby solid phase method according to the general description) wasdissolved in DMF (2 ml) and previously formed Boc-Abu-OPfp (4equivalents) was added and pH was adjusted to 8-8.5 (DIPEA). Thereaction mixture was stirred overnight at room temperature. The productwas isolated by precipitation with ethyl acetate, filtration and dryingin vacuo.

The product was then treated with TFA/CH₂ Cl₂ 1:1 (20 ml), stirred for30 min, evaporated and then treated with diethyl ether (100 ml). Theprecipitation was separated by filtration and dried in vacuo.

The product was purified by reversed phase liquid chromatography.

Purity (HPLC): 99.5% (20.0% acetonitrile in 0.1% TFA, retention time5.94 min at 2 ml/min, detection at 223 nm).

The structure was confirmed by amino acid analysis and FAB MS analysis.

EXAMPLE 6

1-Hmp-4-Hgn-8-Orn-VT [n=2 and Q=H]

The peptide was synthesised according to the general description.2-hydroxy-mercaptopropionic acid[8- (p-methoxy)benzyl] was used forposition 1. Purity (HPLC): 98.5% (14.4% acetonitrile in 0.1% TFA,retention time 5.83 min at 2 ml/min, detection at 223 nm).

The structure was confirmed by amino acid analysis and FAB MS analysis.

EXAMPLE 7

1-Hmp-4-Hgn-8-Dab-VT [n=2 and Q=M]

The peptide was synthesised according to the general description.2-hydroxy-mercaptopropionic acid[S-(p-methoxy)benzyl] was used forposition 1. Purity (HPLC): >99% (18.0% acetonitrile in 0.1% TFA,retention time 4.98 rain at 2 ml/min, detection at 223 nm).

The structure was confirmed by amino acid analysis and FAB MS analysis.

PHARMACOLOGICAL TESTS

Vasotocin derivatives according to the invention have been tested forpotency of both blood pressure and antidiuretic activity in a so-called4-point test, i.e. the activity of the test substances has been relatedto a standard preparation (AVP=argininevasopressin), and the effects oftwo dose levels for each substance have been analysed. In addition,three pressor-specific VT derivatives according to our previousapplication SE 8703855-0 have been tested for a comparison, namely1-Hmp-2-Phe-S-Orn-VT (compound 2 in Table 1), 1-Hmp-2-Phe-S-Dab-VT(compound 3 in Table 1), and 1-Hmp-2-Phe-S-Dab(Ala)-VT (compound 5 inTable 1).

Blood pressure tests were carried out on anaesthetised Sprague Dawleyrats (about 250 g), previously treated with dibenamine (Dekanski, J.,1952. Br. J. Pharmacol. 7, 567). Maximal blood pressure increase afterintravenous injections of peptide was used as a measure of the effect,expressed as intensity.

In addition to potency determination based-on effect intensity, ameasure of the length of the effect has been stated (index ofpersistence (I.P.), Pliska, V., 1966. Arzheim. Forech. 16, 886). Thisdimensionless factor is a measure of the effect duration of therespective analog in relation to the standard AVP.

Antidiuretic potency was determined with the aid of anaesthetisedwater-loaded Sprague Dawley rats (200 g) (Larsson, L. E., Lindeberg, G.,Melin, P. and Pliska, V., 1978, J. Mad. Chem. 21, 353). Maximal increaseof urine conductivity after intravenous injections was used as effectparameter.

In these two tests, a comparison was made between the effects of therespective derivative and the effect of a standard preparation, AVP, andpotency was determined with the aid of a 4-point test and is indicatedin international units per micromole (IU/μmole) (Sturmer, E., inHandbook of Expermimental Pharmacology, 1966, Vol 23, pp 130-189).

The specificity in respect of blood pressure is indicated by the ratioof potency blood pressure/potency antidiuresis (BP/AD).

The pharmacological results are given in Table 1.

From Table 1 it appears that the compounds according to the inventionretain a very high potency in respect of blood pressure increase andeffect duration.

By the introduction of homoglutamine or homocitrulline at position 4 theantidiuretic activity has been practically eliminated. Thus, the presentinvention is unique in that the pressor specificity (ratio of bloodpressure to antidiuretic activity) has been increased approximately 2 to10 times in comparison to the already pressor specific derivatives ofour SE 8703855-0 (modifications at positions 1, 2 and 8 of the parentmolecule; see Table 1).

The combination of this modification with previously made substitutionsat positions 1, 2 and 8 has led to analogs with high potency, longduration of action and extreme pressor specificity. Thus, based on theanimal experiments presented, the new substances may, in therapy beexpected to completely lack any water accumulating effect(antidiuretic), thus totally avoiding the risk of water intoxications ofthe patients.

EXAMPLE OF THE PREPARATION OF A PHARMACEUTICAL COMPOSITION

The VT derivative is dissolved in distilled water together withmannitol. The solution is poured into an ampoule, subjected tofreeze-drying and sealed. The contents in the ampoule can then whendesired, be diluted with an isotonic saline solution to a concentrationsuitable for administration.

                                      TABLE 1                                     __________________________________________________________________________                               BLOOD PRESSURE BP                                                                   I.P (measure                                                                         ANTIDIURESIS                                                                           BP/AD                                                         of duration                                                                          AD       (measure of                  ANALOG                     IU/μmole                                                                         of effect)                                                                           IU/μmole                                                                            specificity)                 __________________________________________________________________________      AVP (Reference)          614 ± 25                                                                         1.0    620 ± 54                                                                            1.0                            1-Hmp-2-Phe-8-Orn-VT     421 ± 41                                                                         3.1 ± 1.3                                                                         9.4 ± 1.1                                                                           45                             1-Hmp-2-Phe-8-Dab-VT     657 ± 32                                                                         2.7 ± 0.6                                                                         18 ± 2.1                                                                            37                             1-Hmp-2-Phe-4-Hgn-8-Dab-VT (Ex. 1(SEQIDNO:2))                                                          214 ± 6                                                                          2.3 ± 0.5                                                                         0.3 ± 0.02                                                                          713                            1-Hmp-2-Phe-8-Dab(Ala)-VT                                                                              360 ± 31                                                                         6.7 ± 1.5                                                                         4.3 ± 0.3                                                                           84                             1-Hmp-2-Phe-4-Hgn-8-Dab(Ala)-VT (Ex. 2)                                                                117 ± 6                                                                          6.6 ± 1.0                                                                         0.2 ± 0.02                                                                          585                            1-Hmp-2-Phe-4-Hgn-8-Dab(Abu)-VT (Ex. 3)                                                                163 ± 15                                                                         8.6 ± 2.3                                                                         0.2 ± 0.01                                                                          858                            1-Hmp-2-Phe-4-Hci-8-Dab-VT (Ex. 4SEGIDNO:3)                                                            157 ± 13                                                                          1.7 ± 0.05                                                                       0.3 ± 0.05                                                                          523                            1-Hmp-2-Phe-4-Hci-8-Dab(Abu)-VT (Ex. 5)                                                                67 ± 5                                                                           3.6 ± 0.7                                                                         0.2 ± 0.04                                                                          335                          10.                                                                             1-Hmp-4-Hgn-8-Orn-VT (Ex. 6) Seq.ID.No. 4                                                              473 ± 62                                                                         7.3 ± 1.8                                                                         1.0 ± 0.2                                                                           473                            1-Hmp-4-Hgn-8-Dab-VT (Ex. 7)                                                                           536 ± 53                                                                         3.8 ± 0.8                                                                         2.9 ± 0.5                                                                           185                          __________________________________________________________________________

    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 5                                                  (2) INFORMATION FOR SEQ ID NO:1:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: circular                                                        (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                    (B) LOCATION: 1                                                              (D) OTHER INFORMATION: /note="Phe or Tyr"                                     (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 3                                                               (D) OTHER INFORMATION: /note="Homoglutamine or                                homocitrulline"                                                               (ix) FEATURE:                                                                 (A) NAME/KEY: Disulfide-bond                                                  (B) LOCATION: 1..5                                                            (D) OTHER INFORMATION: /note="Position 1 contains an                          N-linked hydroxymercaptopropionic acid residue,                               which is S- linked to the 5-Cys."                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 7                                                               (D) OTHER INFORMATION: /note="Dpr, Dbu or Orn"                                (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                       XaaIleXaaAsnCysProXaaGly                                                      1 5                                                                           (2) INFORMATION FOR SEQ ID NO:2:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: circular                                                        (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 3                                                               (D) OTHER INFORMATION: /note="Homoglutamine"                                  (ix) FEATURE:                                                                  (A) NAME/KEY: Disulfide-bond                                                 (B) LOCATION: 1..5                                                            (D) OTHER INFORMATION: /note="Position 1 contains an                          N-linked hydroxymercaptopropionic acid residue,                               which is S- linked to the 5-Cys."                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 7                                                               (D) OTHER INFORMATION: /note="Dbu"                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                       PheIle XaaAsnCysProLysGly                                                     15                                                                            (2) INFORMATION FOR SEQ ID NO:3:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: circular                                                        (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 3                                                                (D) OTHER INFORMATION: /note="Homocitrulline"                                (ix) FEATURE:                                                                 (A) NAME/KEY: Disulfide-bond                                                  (B) LOCATION: 1..5                                                            (D) OTHER INFORMATION: /note="Position 1 contains an                          N-linked hydroxymercaptopropionic acid residue,                               which is S- linked to the 5-Cys."                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 7                                                                (D) OTHER INFORMATION: /note="Dbu"                                           (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                       PheIleXaaAsnCysProLysGly                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:4:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: circular                                                        (ii) MOLECULE TYPE: peptide                                                    (ix) FEATURE:                                                                (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 3                                                               (D) OTHER INFORMATION: /note="Homoglutamine"                                  (ix) FEATURE:                                                                 (A) NAME/KEY: Disulfide-bond                                                  (B) LOCATION: 1..5                                                            (D) OTHER INFORMATION: /note="Position 1 contains an                          N-linked hydroxymercaptopropionic acid residue,                               which is S- linked to the 5-Cys."                                             (ix) FEATURE:                                                                  (A) NAME/KEY: Modified-site                                                  (B) LOCATION: 7                                                               (D) OTHER INFORMATION: /note="Orn"                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                       TyrIleXaaAsnCysProLysGly                                                      15                                                                            (2) INFORMATION FOR SEQ ID NO:5:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 8 amino acids                                                     (B) TYPE: amino acid                                                          (D) TOPOLOGY: circular                                                        (ii) MOLECULE TYPE: peptide                                                   (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 3                                                               (D) OTHER INFORMATION: /note="Homoglutamine"                                  (ix) FEATURE:                                                                 (A) NAME/KEY: Disulfide-bond                                                  (B) LOCATION: 1..5                                                            (D) OTHER INFORMATION: /note="Position 1 contains an                          N-linked hydroxymercaptopropionic acid residue,                               which is S- linked to the 5-Cys."                                             (ix) FEATURE:                                                                 (A) NAME/KEY: Modified-site                                                   (B) LOCATION: 7                                                               (D) OTHER INFORMATION: /note="Dbu"                                            (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                       TyrIleXaaAsnCysProXaaGly                                                      15                                                                        

We claim:
 1. A vasotocin derivative of the formula ##STR7## wherein Hmpis a 2-hydroxy-3-mercaptopropionic acid residue of the formula ##STR8##Z is Phe, Y is Hgn, andX is ##STR9## wherein Q is H and n is
 2. 2. Avasotocin derivative of the formula ##STR10## wherein Hmp is a2-hydroxy-3-mercaptopropionic acid residue of the formula ##STR11## Z isPhe, Y is Hgn, andX is ##STR12## wherein n is 2 and Q is alanyl.
 3. Avasotocin derivative of the formula ##STR13## wherein Hmp is a2-hydroxy-3-mercaptopropionic acid residue of the formula ##STR14## Z isPhe, Y is Hgn, andX is ##STR15## wherein n is 2 and Q isL-2-aminobutyryl.
 4. A vasotocin derivative of the formula ##STR16##wherein Hmp is a 2-hydroxy-3-mercaptopropionic acid residue of theformula ##STR17## Z=Phe, Y=Hci, andX is ##STR18## wherein n is 2 and Qis H.
 5. A vasotocin derivative of the formula ##STR19## wherein Hmp isa 2-hydroxy-3-mercaptopropionic acid residue of the formula ##STR20## Zis Tyr, Y is Hgn, andX is ##STR21## wherein n is 3 and Q is H.